Pilot and definitive studies to evaluate Insertional Mutagenesis

评估插入诱变的试点和最终研究

• 批准号: 8428966
• 负责人: LU TAYLOR
• 金额: $ 14万
• 依托单位: BATTELLE CENTERS/PUB HLTH RES & EVALUATN
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-03 至 2013-02-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8428966
• 关键词: Adverse effects; Alleles; Amino Acids; Architecture; Bone Marrow; Bone Marrow Transplantation; Cells; Chemicals; Contracts; Control Animal; DNA Sequence; Data; Data Set; Development; Dose; Enhancers; Ensure; Environmental Exposure; Evaluation; Exposure to; Future; Gagging; Genome; Goals; Hazard Identification; Hazardous Chemicals; Health; Heightened Cancer Risk; Hematopoietic stem cells; Human; Insertional Mutagenesis; Location; Modeling; Modification; Mus; Mutation; National Toxicology Program; Open Reading Frames; Outcome; Pilot Projects; Plasmids; Positioning Attribute; Process; Property; Public Domains; Retroviral Vector; Risk Assessment; Risk Factors; Safety; Site; Specific qualifier value; Testing; Toxic effect; Toxicity Tests; Transgenes; United States Food and Drug Administration; cellular transduction; design; disorder prevention; enhanced green fluorescent protein; leukemia; promoter; public health research; sound; vector

The purpose of this contract is to conduct studies, which will help the National Toxicology Program (NTP) in the toxicologic characterization associated with short-term exposures to a variety of chemicals. The studies are designed to identify possible target organs of toxicity and differences in sensitivity between sexes and species of animals and dose-response relationships, and possible mechanism of toxicity. Data from prechronic studies will be used by the NTP to characterize and report the toxicity of chemicals studied and for establishment of dose levels of chemicals selected for subsequent long-term carcinogenicity studies. The studies in genetically modified mouse models are designed to validate the use of models as a replacement of the two-year mouse bioassay and to obtain information about mechanisms involved in tumorgenesis. The transgenic models are also used prospectively to evaluate chemicals for their toxicologic potential. Toxicogenomic studies are designed to determine whether the use of genomic technology can detect potential carcinogens in a shorter time frame. The following studies have been completed or are ongoing during FY 2006: RNA isolation for Toxicogenomic Variability Study: RNA is being isolated from sentinel Fischer 344 rats of varying ages from two different laboratories to determine the variability of Differential Gene Expression (DGE) in liver. This study is ongoing and the isolated hepatic RNA will be sent to another contract lab for gene expression profiling. Toxicogenomic evaluation of four rat liver carcinogens and three non-carcinogens in male Fischer 344 rats: The in-life portion of this study has been completed by the lab. Liver histopathology, glutathione, clinical pathology, hepatic RNA isolation and subsequent microarray profiling, liver proteomics and serum multiple analyte profiles (MAPs) will be determined in this study. Perinatal study of polybrominated diphenyl ether congener DE-47 in CB6F1-Tg(HRAS2) transgenic mice: A pilot study is being performed at the lab and the results are expected in FY 2007. Six Month Safety Study of Chitosan: The in-life portion of this study is ongoing and will investigate the effect of chitosan administered in dosed feed on bone osteopenia and osteoporosis, on fat and calcium absorption, and on the status of fat soluble vitamins (A, K, E, and 25-hydroxy vitamin D metabolites) and other toxicological effects in Sprague-Dawley rats. QT Prolongation in Beagle Dog via Implantable Telemetry: This study has been awarded to the lab to determine the sensitivity and specificity of the conscious canine radio telemetry model for the evaluation of QT interval prolongation using six drugs (Sotalol, Terfenedine, Bepridil, Loratadine, Lovastatin, and Diltiazem). . If successful, definitive studies will be extended to examine the sensitivity and specificity of the assay. FDA-NTP Studies of Insertional Mutagenesis - Pilot Study: 12-week pilot study has been awarded to the lab to develop and validate preclinical model for assessing risk of retroviral vector-mediated insertional tumorgenesis. The study is proposed to start in FY 2007. 39-week study of Senna in p53 (+/-) transgenic mice: Study has been awarded to the lab to determine the toxic/neoplastic responses of Senna in heterozygous p53 (+/-) transgenic mouse model. Studies will start in FY-2007. Proficiency Evaluation in Support of the Murine Protocol Section of the Exposure Biology Program: The goal of this project is to develop a panel of biologic response markers for environmental agents (ozone, cigarette smoke, endotoxin, and allergen) that are known to perturb biologic systems resulting in changes in the airway that lead to the development of chronic airway disease. In order to establish a programmatic infrastructure to support these projects we have issued a work assignment to the lab that will be used to establish laboratory proficiency in selected special techniques. Keywords Toxicologic evaluation; Perinatal study; Rats- F344/N; CB6F1-Tg(HRAS2)transgenic mice; Genetically Modified Mouse Models; RNA isolation; Toxicogenomic evaluation; Microarray; Differential Gene Expression (DGE);liver proteomics; serum multiple analyte profiles (MAPs); N-acetyl-p-Aminophenol(APAP); Nitrosodimethylamine; Anthraquinone; Aflatoxin B1; Ascorbic acid; l-tryptophan; Methlyeugenol; Senna; PolyBrominated diphenyl ether congeners; PBDE-47; Carcinogen and Non-carcinogen; RNA Preparation, Chitosan; QT Prolongation; Insertional Mutagenesis; Airway Proficiency, Allylbenzene, Propenylbenzene, Flavor constituents, Methyleugenol, Safrole, Estragole, Isosafrole, Eugenol, Isoeugenol, Myristicin, and Anethole.

该合同的目的是进行研究，这将有助于国家毒理学计划 (NTP) 确定与短期接触各种化学品相关的毒理学特征。这些研究旨在确定可能的毒性靶器官、动物性别和物种之间的敏感性差异、剂量反应关系以及可能的毒性机制。 NTP 将使用慢性前研究的数据来表征和报告所研究化学品的毒性，并确定为后续长期致癌性研究选择的化学品的剂量水平。转基因小鼠模型的研究旨在验证模型是否可以替代两年的小鼠生物测定，并获取有关肿瘤发生机制的信息。转基因模型还前瞻性地用于评估化学品的毒理学潜力。毒理基因组学研究旨在确定使用基因组技术是否可以在更短的时间内检测出潜在的致癌物。 2006 财年期间已完成或正在进行以下研究： 用于毒物基因组变异性研究的 RNA 分离：从两个不同实验室不同年龄的哨兵 Fischer 344 只大鼠中分离 RNA，以确定肝脏中差异基因表达 (DGE) 的变异性。这项研究正在进行中，分离的肝脏 RNA 将被送往另一个合同实验室进行基因表达谱分析。雄性 Fischer 344 大鼠中四种大鼠肝脏致癌物和三种非致癌物的毒理学评估：本研究的活体部分已由实验室完成。本研究将确定肝脏组织病理学、谷胱甘肽、临床病理学、肝脏 RNA 分离和随后的微阵列分析、肝脏蛋白质组学和血清多种分析物谱 (MAP)。多溴二苯醚同源物 DE-47 在 CB6F1-Tg(HRAS2) 转基因小鼠中的围产期研究：一项试点研究正在实验室进行，预计在 2007 财年得出结果。 为期六个月的壳聚糖安全性研究：这项研究的活体部分正在进行中，将研究在剂量饲料中施用壳聚糖对骨质减少和骨质疏松症的影响。 骨质疏松症，对脂肪和钙的吸收，以及脂溶性维生素（A、K、E 和 25-羟基维生素 D 代谢物）的状态以及 Sprague-Dawley 大鼠的其他毒理学作用。通过植入遥测技术延长比格犬的 QT 间期：这项研究已授予实验室，以确定有意识的犬无线电遥测模型的敏感性和特异性，用于评估使用六种药物（索他洛尔、特非尼定、苄普地尔、氯雷他定、洛伐他汀和地尔硫卓）评估 QT 间期延长。 。如果成功，将扩大确定性研究以检查该测定的敏感性和特异性。 FDA-NTP 插入诱变研究 - 试点研究：实验室已获得为期 12 周的试点研究，以开发和验证临床前模型，以评估逆转录病毒载体介导的插入肿瘤发生的风险。该研究计划于 2007 财年开始。 在 p53 (+/-) 转基因小鼠中进行为期 39 周的番泻叶研究：该实验室已获得一项研究，以确定番泻叶在杂合 p53 (+/-) 转基因小鼠模型中的毒性/肿瘤反应。研究将于 2007 财年开始。支持暴露生物学计划的小鼠方案部分的熟练程度评估：该项目的目标是开发一组针对环境因素（臭氧、香烟烟雾、内毒素和过敏原）的生物反应标记物，这些环境因素已知会扰乱生物系统，导致气道变化，从而导致慢性气道疾病的发展。为了建立支持这些项目的计划基础设施，我们向实验室发出了一项工作任务，该任务将用于建立实验室对选定特殊技术的熟练程度。 关键词 毒理学评价；围产期研究；大鼠- F344/N； CB6F1-Tg(HRAS2)转基因小鼠；转基因小鼠模型； RNA分离；毒理基因组学评估；微阵列；差异基因表达（DGE）；肝脏蛋白质组学；血清多种分析物谱 (MAP)； N-乙酰基-对氨基苯酚(APAP)；亚硝基二甲胺；蒽醌；黄曲霉毒素B1；抗坏血酸; L-色氨酸；甲基丁香酚；番泻叶；多溴二苯醚同系物；多溴二苯醚-47；致癌物和非致癌物； RNA制备、壳聚糖； QT间期延长；插入诱变；气道熟练度、烯丙基苯、丙烯基苯、风味成分、甲基丁子香酚、黄樟素、黄芪甲醚、异黄樟素、丁子香酚、异丁子香酚、肉豆蔻甙和茴香脑。